Urologic Chronic Pelvic Pain Syndrome (UCPPS) is a debilitating urologic condition characterized by bladder/pelvic pain and urinary symptoms such as urgency and frequency. Treating UCPPS remains a serious challenge for clinicians in part because the mechanisms of the disease are not well understood. This challenge is even greater when patients have pain outside the pelvis and/or comorbid pain syndromes, as the central nervous system (CNS) may play a significant role in their symptoms, a phenomenon we term ?centralized? pain. The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network was initiated in response to these challenges. In a site-specific study conducted during first phase of MAPP, we showed that when immune cells isolated from UCPPS patients are stimulated ex vivo, the resulting inflammatory response distinguishes patients with localized pain from those with a more widespread pain presentation. In the second phase of MAPP, samples of stimulated whole blood have been collected on the vast majority of patients in conjunction with functional connectivity magnetic resonance imaging (fcMRI), psychophysical sensory testing, and a comprehensive battery of patient reported outcomes. However, as the second phase of MAPP draws to a close, funding is not available to analyze these stimulated samples. In the current project, we propose to complete this critical work and elucidate how inflammation influences the CNS in UCPPS. We have assembled a team of MAPP investigators and added expertise in clustering and classification bioinformatics in order to address three scientific aims. AIM 1: Validate the inflammatory phenotype of UCPPS. (A) We will replicate and extend our previous cross-sectional findings indicating that stimulated inflammatory responses may be able to classify UCPPS patients with greater clinical evidence of centralized pain (test n = 200, validation n = 200). (B) We will determine if longitudinal changes in genitourinary symptoms and pain over 18 months are paralleled by changes in the stimulated inflammatory responses in a subset of these patients (n = 250). AIM 2: Identify a neurobiological signature of the inflammatory phenotype using fcMRI and psychophysical sensory testing. (A) We will conduct cross-sectional analyses to identify neurobiological correlates of the inflammatory phenotype (test n = 200, validation n = 200). (B) We will create longitudinal models to determine if identified fcMRI and psychophysical outcomes co-vary with inflammation over time (n = 250). AIM 3: Identify biotypes of UCPPS using combined inflammatory, neuroimaging, psychophysical, and clinical data. We will use bioinformatics techniques including canonical correlation analysis and hierarchical clustering to attempt to define unique, latent, biotypes of UCPPS. We hypothesize that these biotypes will reflect different clinical phenotypes and may be useful for predicting treatment responses. The impact of these studies is that they may lead to novel therapeutic targets and tailored treatments for UCPPS by elucidating an important and under-studied mechanism of UCPPS symptomology.